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Elife ; 82019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050646


During development cells become restricted in their differentiation potential by repressing alternative cell fates, and the Polycomb complex plays a crucial role in this process. However, how alternative fate genes are lineage-specifically silenced is unclear. We studied Ultrabithorax (Ubx), a multi-lineage transcription factor of the Hox class, in two tissue lineages using sorted nuclei and interfered with Ubx in mesodermal cells. We find that depletion of Ubx leads to the de-repression of genes normally expressed in other lineages. Ubx silences expression of alternative fate genes by retaining the Polycomb Group protein Pleiohomeotic at Ubx targeted genomic regions, thereby stabilizing repressive chromatin marks in a lineage-dependent manner. Our study demonstrates that Ubx stabilizes lineage choice by suppressing the multipotency encoded in the genome via its interaction with Pho. This mechanism may explain why the Hox code is maintained throughout the lifecycle, since it could set a block to transdifferentiation in adult cells.

Cell Rep ; 14(4): 850-860, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26776518


Feeding is an evolutionarily conserved and integral behavior that depends on the rhythmic activity of feeding muscles stimulated by specific motoneurons. However, critical molecular determinants underlying the development of the neuromuscular feeding unit are largely unknown. Here, we identify the Hox transcription factor Deformed (Dfd) as essential for feeding unit formation, from initial specification to the establishment of active synapses, by controlling stage-specific sets of target genes. Importantly, we found Dfd to control the expression of functional components of synapses, such as Ankyrin2-XL, a protein known to be critical for synaptic stability and connectivity. Furthermore, we uncovered Dfd as a potential regulator of synaptic specificity, as it represses expression of the synaptic cell adhesion molecule Connectin (Con). These results demonstrate that Dfd is critical for the establishment and maintenance of the neuromuscular unit required for feeding behavior, which might be shared by other group 4 Hox genes.

Proteínas de Drosophila/metabolismo , Proteínas de Homeodomínio/metabolismo , Neurônios Motores/metabolismo , Junção Neuromuscular/metabolismo , Animais , Anquirinas/metabolismo , Conectina/metabolismo , Drosophila , Proteínas de Drosophila/genética , Comportamento Alimentar , Proteínas de Homeodomínio/genética , Neurônios Motores/citologia , Neurogênese , Junção Neuromuscular/crescimento & desenvolvimento
PLoS Genet ; 9(9): e1003720, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24068944


The Drosophila embryonic gonad is assembled from two distinct cell types, the Primordial Germ Cells (PGCs) and the Somatic Gonadal Precursor cells (SGPs). The PGCs form at the posterior of blastoderm stage embryos and are subsequently carried inside the embryo during gastrulation. To reach the SGPs, the PGCs must traverse the midgut wall and then migrate through the mesoderm. A combination of local repulsive cues and attractive signals emanating from the SGPs guide migration. We have investigated the role of the hedgehog (hh) pathway gene shifted (shf) in directing PGC migration. shf encodes a secreted protein that facilitates the long distance transmission of Hh through the proteoglycan matrix after it is released from basolateral membranes of Hh expressing cells in the wing imaginal disc. shf is expressed in the gonadal mesoderm, and loss- and gain-of-function experiments demonstrate that it is required for PGC migration. Previous studies have established that the hmgcr-dependent isoprenoid biosynthetic pathway plays a pivotal role in generating the PGC attractant both by the SGPs and by other tissues when hmgcr is ectopically expressed. We show that production of this PGC attractant depends upon shf as well as a second hh pathway gene gγ1. Further linking the PGC attractant to Hh, we present evidence indicating that ectopic expression of hmgcr in the nervous system promotes the release/transmission of the Hh ligand from these cells into and through the underlying mesodermal cell layer, where Hh can contact migrating PGCs. Finally, potentiation of Hh by hmgcr appears to depend upon cholesterol modification.

Movimento Celular/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/embriologia , Subunidades gama da Proteína de Ligação ao GTP/genética , Proteínas Hedgehog/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Animais , Blastoderma/crescimento & desenvolvimento , Blastoderma/metabolismo , Proteínas de Drosophila/metabolismo , Embrião não Mamífero/metabolismo , Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica no Desenvolvimento , Células Germinativas/citologia , Células Germinativas/metabolismo , Gônadas/embriologia , Proteínas Hedgehog/metabolismo , Proteínas de Grupo de Alta Mobilidade , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ligação Proteica , Transdução de Sinais , Terpenos/metabolismo , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
EMBO J ; 31(15): 3323-33, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22781127


Precise gene expression is a fundamental aspect of organismal function and depends on the combinatorial interplay of transcription factors (TFs) with cis-regulatory DNA elements. While much is known about TF function in general, our understanding of their cell type-specific activities is still poor. To address how widely expressed transcriptional regulators modulate downstream gene activity with high cellular specificity, we have identified binding regions for the Hox TF Deformed (Dfd) in the Drosophila genome. Our analysis of architectural features within Hox cis-regulatory response elements (HREs) shows that HRE structure is essential for cell type-specific gene expression. We also find that Dfd and Ultrabithorax (Ubx), another Hox TF specifying different morphological traits, interact with non-overlapping regions in vivo, despite their similar DNA binding preferences. While Dfd and Ubx HREs exhibit comparable design principles, their motif compositions and motif-pair associations are distinct, explaining the highly selective interaction of these Hox proteins with the regulatory environment. Thus, our results uncover the regulatory code imprinted in Hox enhancers and elucidate the mechanisms underlying functional specificity of TFs in vivo.

Drosophila/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Elementos de Resposta/genética , Fatores de Transcrição/metabolismo , Animais , Animais Geneticamente Modificados , Sítios de Ligação/genética , Drosophila/embriologia , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Genes de Insetos , Código das Histonas/genética , Código das Histonas/fisiologia , Proteínas de Homeodomínio/metabolismo , Modelos Biológicos , Ligação Proteica , Fatores de Transcrição/fisiologia , Ativação Transcricional
Mar Pollut Bull ; 56(9): 1609-17, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18649896


Socio-economic development in Europe has exerted increasing pressure on the marine environment. Eutrophication, caused by nutrient enrichment, is evident in regions of all European seas. Its severity varies but has, in places, adversely impacted socio-economic activities. This paper aims to evaluate the effectiveness of recently adopted policies to reduce anthropogenic nutrient inputs to European seas. Nitrogen and phosphorus budgets were constructed for three different periods (prior to severe eutrophication, during severe eutrophication and contemporary) to capture changes in the relative importance of different nutrient sources in four European seas suffering from eutrophication (Baltic Proper, coastal North Sea, Northern Adriatic and North-Western Black Sea Shelf). Policy success is evident for point sources, notably for P in the Baltic and North Seas, but reduction of diffuse sources has been more problematic.

Conservação dos Recursos Naturais/métodos , Ecossistema , Eutrofização/fisiologia , Modelos Teóricos , Nitrogênio/análise , Fósforo/análise , Europa (Continente) , Oceanos e Mares
Leuk Lymphoma ; 46(9): 1357-63, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16109615


Drug resistance can be caused by ATP-binding-cassette (ABC)-transporters which function as outward pumps for chemotherapeutic drugs. The aim of the present study was to analyze the association between eight ABC-transporters (BCRP, MDR1, SMRP, MRP1, MRP2, MRP3, MRP4, and MRP5) and in vitro drug resistance. Leukemic cells from 52 children with previously untreated acute leukemia (ALL: n=37; AML: n=15) were analysed. The expression of the ABC-transporters was measured by TaqMan real-time PCR. In vitro drug resistance to cytarabine, vincristine, tioguanine, daunorubicin, etoposide, dexamethasone, and prednisone was analysed with methyl-thiazol-tetrazolium (MTT) assays.MDR1 was weakly associated with resistance to vincristine (p<0.05) in AML samples. No other correlation between an ABC-transporter and a higher in vitro drug resistance was found. In vitro drug resistance was not associated with the simultaneous expression of a larger number of ABC-transporters.MTT assays are a widely used and validated method to analyse in vitro drug resistance but they may not be a useful tool to detect resistance which is caused by drug efflux in patient samples. If that is the case, MTT assays and the expression of ABC-transporters could provide complementary information on the drug resistance profile of patients with acute leukemia.

Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Leucemia Mieloide Aguda/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Dose Letal Mediana , Masculino